title: Essential requirements of zoledronate-induced cytokine and γδ T cell proliferative responses.
abstract: The potent nitrogen-containing bisphosphonate zoledronate inhibits farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway that is often hyperactive in malignant cells. Zoledronate activates human Vγ9Vδ2 T cells, which are immune sentinels of cell stress and tumors, through upstream accumulation of the cognate Ag isopentenyl pyrophosphate. IL-18 was shown to enhance zoledronate-induced γδ T cell activation. Although monocytes have been considered important accessory cells that provide the Ag isopentenyl pyrophosphate, CD56(bright)CD11c(+) NK cells were postulated to mediate the costimulatory effects of IL-18. We report in this article that downstream depletion of geranylgeranyl pyrophosphate (GGPP), which is required for protein prenylation, caused cell stress in monocytes, followed by caspase-1-mediated maturation and release of IL-18, which, in turn, induced γδ T cell CCL2. Likewise, zoledronate caused a substantial delay in γδ T cell expansion, which could be skipped by GGPP supplementation. Moreover, repletion of GGPP, which prevented acute zoledronate toxicity, and supplementation with IL-18, which strongly upregulated IL-2Rα (CD25) and favored the central memory phenotype, were sufficient to enable zoledronate-induced expansion of highly purified γδ T cells, even when starting cell numbers were as low as 10(4) γδ T cells. Our study reveals essential components of γδ T cell activation and indicates that exogenous IL-18, which can directly costimulate γδ T cells, eliminates the need for any accessory cells. Our findings will facilitate the generation of robust γδ T cells from small blood or tissue samples for cancer immunotherapy and immune-monitoring purposes.
authors.affiliation: Cell Therapy Unit, Department of Urology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Nussbaumer
authors.forename: Georg
authors.initials: G
authors.lastname: Gruenbacher
authors.forename: Hubert
authors.initials: H
authors.lastname: Gander
authors.forename: Juliana
authors.initials: J
authors.lastname: Komuczki
authors.forename: Andrea
authors.initials: A
authors.lastname: Rahm
authors.forename: Martin
authors.initials: M
authors.lastname: Thurnher
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism / Q000494:pharmacology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004164:Diphosphonates; D007093:Imidazoles; D020382:Interleukin-18; D053645:Interleukin-2 Receptor alpha Subunit; D011106:Polyisoprenyl Phosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid; D020170:Caspase 1; C002963:geranylgeranyl pyrophosphate